(1) Field of the Invention
The present invention relates generally to softgels or soft gelatin capsules and fill compositions therefor, and in particular to a soft gelatin capsule that contains a highly concentrated solution of ibuprofen in its free form.
(2) Description of the Prior Art
U.S. Pat. No. 4,690,823 to Lohner et al. describes a process for manufacturing ibuprofen-containing soft gelatin capsules in which up to 30 parts by weight of ibuprofen in free form is dissolved in from 70 to 85 parts by weight of polyoxyethylene-polyoxypropylene polymer or in a mixture of from 30 to 76 parts by weight of a polyalkylene glycol and from 7 to 40 parts by weight of a surfactant having a very rapid and high bio-availability of the active ingredient. Preferred suitable surfactants include, for example, polyoxyethyleneglycerol trihydroxystearate, polyoxyethylene (C.sub.12 -.sub.18)-fatty alcohol ethers, polyoxyethylene stearate, polyoxyethylenesorbitan mono(C.sub.12 -.sub.18)-fatty acid esters, and polyoxyethylene-polyoxypropylene polymer.
In the Lohner et al. process, up to 30 parts by weight of free form ibuprofen is dissolved by heating the free form ibuprofen with the selected solvent at a temperature of 45.degree. to 60.degree. C. If a concentration of ibuprofen greater than the maximum 30 parts by weight possible in solution is desired, up to 40 parts additional parts by weight of ibuprofen may also be suspended in the fill.
Softgel fills containing high concentrations of ibuprofen as a mixture of ibuprofen in free form and its salts are described in U.S. Pat. Nos. 5,071,643 and 5,360,615 to Yu et al. These fill formulations may be liquid, semi-solid or solid, and are formed by mixing 40-80% by weight ibuprofen, 0.1-1.5 moles of hydroxide ion per mole of ibuprofen, 1-20% by weight water, and 4-12% by weight glycerine or propylene glycol in polyethylene glycol. Solubility of the ibuprofen salts is further enhanced 2-10% by the further addition of 3-10% by weight of glycerin, or propylene glycol or 1-20% by weight of polyvinylpyrrolidone.
The preferred average molecular weight of the polyvinylpyrrolidone is 10,000-100,000. Higher percentages of above 5% polyvinylpyrrolidone, and higher molecular weight polyvinylpyrrolidone are used to prepare semi-solid and solid formulations for suppositiories, two piece capsules, and tablets.
Upon mixing under the conditions described by Yu et al., the polyethylene glycol acts to dissolve the free form of the ibuprofen; the hydroxyl ions source, e.g., sodium hydroxide or potassium hydroxide, partially forms an ibuprofen salt, and the water forms a solvation sphere around the acid salt permitting it to go into solution in the polyethylene glycol.
While softgel fill compositions containing ibuprofen salts can be produced by the above procedures, there is still a need for liquid softgel fill formulations with high concentrations, i.e., greater than 30% by weight, of ibuprofen in solution in its free acid form. In particular, there is a need for highly concentrated solutions containing ibuprofen in its free form that do not adversely affect the softgel capsules over an extended period of time.